To be ophthalmologically acceptable, a formulation must process a number of characteristics to comply with the general FDA requirements of being safe and effective. In that eyes are quite sensitive to pain, the formulation must be developed such that it causes little to no discomfort or stinging when administered. This feature is particularly important to insure user complaince and important in that such formulations are often administered in order to relieve pain or inflammation. The ophthalmic use of NSAID compounds was disclosed in U.S. Pat. No. 4,454,151, where NSAID compounds (such as those described in U.S. Pat. Nos. 4,089,969; 4,232,038; 4,087,539 and 4,097,579) were exemplified in formulation with NaH.sub.2 PO.sub.4.H.sub.2 O, Na.sub.2 HPO.sub.4.H.sub.2 O, NaCl, benzalkonium chloride ("BAC") and sterilized water. While the formulations described in the '151 patent were efficacious, a complex was found to form between the NSAID and the BAC.
Due to the formation of this complex, the formulations did not have the stability desired for shelf life in commercial applications. A reasonable minimum shelf life is at least about one year, representing sufficient time to package, ship, and store a formulation without having to replace expired stock too frequently.
An ophthalmic suspension containing a particular NSAID is disclosed in U.S. Pat. No. 4,087,538 issued May 2, 1978. The suspension is aqueous based and can include benzalkonium chloride. Another ophthalmic formulation is disclosed in U.S. Pat. No. 4,559,343 issued Dec. 17, 1985. The formulation is aqueous based and includes an NSAID and a benzalkonium chloride preservative. A somewhat similar ophthalmic formulation is disclosed in U.S. Pat. No. 4,607,038 issued Aug. 19, 1986. This formulation includes a specific NSAID (pranoprofen) in an aqueous based formula with a known preservative. U.S. Pat. No. 4,474,751 issued Oct. 2, 1984 discloses ophthalmic formulations which gel in the eye in order to increase the bioavailability of the drug. The '751 patent discloses a large number of different active ingredients and excipient material. When this disclosure is taken in view of the other patents discussed above and the publications cited in each of them, the vast number of different ways of creating an ophthalmic formulation becomes apparent. Although there may be a considerable number of possible formulations and variations thereof, only certain specific formulations will meet all the requirements for being ophthalmologically acceptable.
In general, an ophthalmic formulation contains an active compound and various ophthalmologically acceptable excipients, in the form of a solution, an ointment, a suspension, etc. In order for an excipient to be ophthalmologically acceptable, it must be non-irritating to the eye in combination with other excipients and an active ingredient. The excipients must not prevent the active ingredient from penetrating the blood-aqueous barrier and/or difusing through the various ocular substructures to the site where it is pharmacologically active. The excipients can interact with each other or the active drug. Accordingly, care in formulating is required in that so many materials may be used. These materials generally include a tonicifier, a preservative, a surfactant, a buffering system, a chelating agent, a viscosity agent as well as other stabilizing agents. Ophthalmic formulations must be sterile and must be preserved with an effective anti-microbial agent.
Organo-mercurials (e.g., thimerosal, phenylmercuric acetate and phenylmercuric nitrate) have been used extensively as the preservative in ophthalmic solutions. These compounds, however, pose difficulties due to potential mercury toxicity as well as poor chemical stability. Benzalkonium chloride, a quaternary ammonium compound, has been widely used in ophthalmic solutions, and is considered to be the preservative of choice. However, BAC has typically been considered to be incompatible with anionic drugs (e.g., salicylates or nitrates, etc.) and can be inactivated by surfactants.
Many NSAIDs such as ketorolac, indomethacin, flurbiprofen and suprofen) are being developed for ocular use because of their activity as anti-inflammatory agents as well as their ability to prevent cystoid macular edema.
These NSAIDs have proven to be incompatible with quaternary ammonium compounds such as BAC because they can form a complex with them, rendering the preservative less available to serve its function, as is the case with other ophthalmic drugs that contain a --COOH group. Thus, less preferred preservatives have been used in such ophthalmic formulations. For example, Ocufen Ophthalmic solution, the first NSAID (flurbiprofen) approved by the FDA for ophthalmic use, incorporates thimerosal (with EDTA) as its preservative system.
A need has continued to exist for a stable, clear, antimicrobial preservative effective ophthalmic formulation for NSAIDs alone or with antibiotics using BAC as the preservative, and an improved preservative system for --COOH group containing ophthalmic drugs.